SUMMARY The latent reservoir in resting CD4+ T cells is viewed as a major obstacle to curing HIV-1 infection. The resting CD4+ T cell population, however, is heterogeneous and includes nave (TN), stem cell-like memory, central memory (TCM), transitional memory (TTM), effector memory (TEM), and terminally differentiated cells. Prior studies, largely based on the quantification of HIV-1 in sorted resting CD4+ T cells, suggested that TCM cells, due their relative abundance, retention of proliferative capacity and relatively long life-span (1-12 months), should be regarded as the major reservoir of replication-competent HIV-1. The CD4+ TN cells which are precursors to the memory subsets, are abundant, and have exceptionally long half-lives (1-8 years). HIV-1 DNA is almost always detected in TN cells in both viremic and suppressed individuals, although with a much lower frequency compared to the TCM, TTM and TEM compartments. In light of the low infection rates of CD4+ TN cells, there has been little emphasis on studying the establishment and reversal of latency in these cells. However, for several reasons documented in the Significance, our laboratory has actively investigated HIV-1 reservoirs in TN cells and we made a surprising discovery: although the frequency of HIV-1 infection is lower in TN compared to TCM cells purified from individuals on long-term suppressive ART (as assessed by total HIV-1 DNA), as much, if not more, virus is produced from TN cells after exposure to latency reactivating agents. This finding shows that quantifying HIV-1 DNA alone may not be predictive of the size of the inducible latent reservoir in different T cell subsets, and that greater attention and research efforts should be given to the reservoir of HIV-1 in TN cells. Accordingly, our scientific premise is that TN cells are a major reservoir of replication-competent HIV-1, and we propose mechanistic-driven research to gain novel insights into the biology of the latent reservoir in CD4+ TN cells.